Phenoxyethyl quaternary ammonium salts



Patented Apr. 3, 1951 I w.

7 UNITED STATES PATENT OFFICE 2,547,365 r PHEN OXYETHYL QUA 'IEERNARYAMMONIUM Louis H. Bock, Huntingdon- Valley, and- Leo S. Luskin,Philadelphia, Pa., assignors to Rohm & Haas Company, PhiladelphimPa acorpora-- tion of Delaware 1 I0Drawing, Application Jaim- 28', 1949-,

' SeriaINo.73,438

l y This invention relatesto henoxy'ethylquater- Ilary ammonium salts ofthe formula;

wherein the CeHivis a non-primary alkyl group; i. e., secondary ortertiary, A is hydrogen or the methyl group, Y is a chalcogen of atomicweight 16 to'32, X is; chlorine or bromine, or is an integer from one tothree, and m is an integer from one to two.

The compounds falling within this structure form a. small but uniquegroup of quaternary ammonium salts which are characterized by highbactericidal efliciency and good fungicidal ac-- tion coupled withrelatively low toxicity toward Warm-blooded animals and little, if any,irritation to mucous membranes and other exposed surfaces. They areuseful for destroying growth of bacteria and fungi generally, but areparticularly desirable for pre-operative cleansing of skin, surfacetreatment of Wounds, sterilization of surgical instruments, and thelike. They are effective antiseptics and disinfectants at lowconcentrations. This is particularly true of their action againstGram-positive pathogenic bacteria. They are effective for destroyingodors, particularly those arisingv from putr'efaction, and because oftheir lack of irritation are particularly suitable for spraying insolution for such purposes. The dilute solutions of these compounds arerelatively free of objectionable taste.

The compoundsof this invention are prepared by reacting together inapproximately equivalent weights a compound of the iormula ,5 1" p 1 7ducedr ressure, leaving'a gummy mass. This @qoomonpm was triturated withethyl'acetate to: give a cryssl" 40 talline solid in a yield.o..33parts. Analyses and a compound of the formula @mcmCmmx.

the aboveformula which: may be used are those having such-N-substituents aso caprylphenoxy- A ol ims. (o1. zso-i-ssm) The phenylether halides are represented by phenoxyethyl chloride or bromide andphenoxy ethoxyethyl chloride or bromide, phenylthioethyl chloride orbromide, phenoxyethylthioethyl haleide, and phenylthioethylthioethylhalide.

The solvents which are useful include hydrocarbons such as toluene andxylene, esters such as butyl acetate, nitrohydrocarbons, such asnitromethane, and miscellaneous solvents such as acetonitrile andformamide.

ethyl alcohol, ethylether, isopropyl ether, or'

mixtures of such solvents;

- The reaction is carried out in one or more volatile organic solventsat to 100 C. and the product is obtained either as a residue after:evaporation of solvent or as a crystalline solid," particularly afteradjustment of solvent as to type and/or amount.

Illustrative examples; for the preparation of the compounds of thisinvention follow; 7

. Example 1 There were mixed 68 parts by weight of p-- C 1,1,3,3-tetramethylbutylphenoxyethoxyethyl dimethylamine, 33 parts ofbeta-phenoxyethyl chloride, and SO'parts of 'nitromethane. The mixturewas, stirred and heated at to C. for 88 hours. At this time a titrationfor ionizablechlorine indicated a conversion of 88.5%.

The nitromethane was" distilled 01f under reel showed the producttocorrespond to C2aH44C1NQ3 OH; on, V or 730 against Staphylococcusaureus.

ethyl, "1p 1,3,3 tetramethylbutylphenoxyethyl,- Z.

pi l,,l-,3 etramethylbutylphenoxyethoxyethyl, cus'feca Exam Z3 2Prr'LL33 amethylblliy p amfilhoxyethoxye P v h thyl; 1;,5,5 rin'lethy1pntvlphe oxvethyl, p.- A mixture, was made from; 34o, parts oi z'--;"dusobutrleo-cresoxyethyl, audth like. v as: methyl 4 (f1 I,3;3+tetrem h1 ut lwh Mixtures: of solvents are often particularly usefuli It isdesir-- bromide, and 1084. parts of acetonitrile.

noxyethoxyethyl dimethylamine, 202 parts of beta-phenoxyethyl bromide,200 parts of nitromethane, and 250 parts of acetonitrile. The mixturewas heated at 80 C. to 90 C. for four hours. Ethyl acetate was added tothe mixture as it cooled. Crystals formed and were separated. Solventwas removed therefrom by vacuum evaporation. The crystals resultingcontained 14.58% of bromine compared to the theoretical value of 14.91%for C29H46B1NO3. The product was2-methy1-4-(1,1,3,3-tetramethylbutyDphenoxyethoxyethyl phenoxyethylmethyl ammonium bromide.

It has a phenol coeflicient of about 185 against Salmonella typhi by theF. 'D. A. method and of about 355 against Staphylococcus aureus.

Example 3 A mixture was prepared from 680 parts of pi 1,133tetramethylbutylpbenoxyethoxyethyl di'methvlam'ine', 404 parts ofbeta-phenoxyethyl The mixture was stirred and heated on a hot water bathat about 85 C. for five hours. The reaction mixture was diluted with1800 parts of ethyl acetate and cooled. Crystals formed, w re removed byfiltration, and were dried. Solvent was taken from the filtrate un erreduced oressure and a second crop of crystals was obtained.

The total yield was 812 parts of colorl ss crystals which correspondedin composition to CH3 CH3 Br CH3 CH3 CH3 C H3 The phenol coefficient ofthis compound was determined as 310 with Salmonella typhi and 785 withStaphylococcus 'aureus.

Effective d lutions were determined in trypticase-soy broth forbactericidal (Bo) and bacteriostatic (Bs) e fects as follows: for Staph.aureus, Be 1 to 128,000: Bs 1 to 8,192,000: for S. pyogenes, Be 1 to2.048.000, Bs 1 to 8.192.000; for S. jecalis, Bs 1 to 256,000, Bs 1 to1,024,000: N. catarrhalis, Bc 1 to 1.024.000, Rs 1 to 2,048,000: and forCl. welchiz', Be 1 to 512,000, Bs 1 to 512,000.

Fungitoxicity tests were made by the slide germination technique withMacrosporium sarcinaeforme (Cav.) as the test organism. At a dilution of1 to 200,000 of the above compound,

there was 100% inhibition of germination.

Toxicity toward warm-blooded animals was determined by oraladministration of a 20%.

The milligrams of the compound per kilogram of body weight which aqueoussolution to rats.

killed half of the test animals was 750.

Dilute solutions have been found non-irritating to nose, throat, andeye.

Example} phenoxyethyl bromide, and"63'-part s. of ethyl acetate. Themixture was stirred and heated under reflux for two hours. There wasadded 830 parts of ethyl acetate and the mixture cooled. There wasobtained a crystalline product in an amount of 445 parts.

For the preparation of the above amine there were mixed 139 parts of.o-caprylphenoxyethyl; chloride, 310 parts of a 25% aqueousdimethylamine solution, 2.1101224 parts "of sodium hydroxide in aconcentrated aqueous solution. The mixture was heated in an autoclavefor five hours at 140-155 c. at a pressure of 70-100 1bs.""The mixturewas cooled, separated, and distilled. The desired chloride was obtainedat 160 C. to 180 C./4 mm.

The product resulting from the reaction of thecaprylphenoxyethyldimethylamineand phenoxyethyl bromide was found tocorrespond by It had a phenol coeflicient of about 350 againstSalmonella typhi and of about 750 against Staphylococcus aureus.

Example 5 There were mixed 101 parts of diisobutylphenoxyethoxyethyldimethylamine, '74 parts. .of phenoxyethoxyethyl bromide, and 1'75partsof acetonitrile. The mixture was stirred and" heated for 6.25 hoursunder reflux. The mi'x ture was then chilled. Crystalsidrmed and werefiltered oil. The yield was 121 parts of a compound having the formulaThere were mixed 335 parts by weightof ocaprylphenoxyethyldimethylamine, 260 parts of Til on, on,

This" product had a, phenol, coefficient of goo, against Salmonellatyphi and 600against Staphylococcus aureus.

Example 6 There were mixed 84 parts of diisobutyl-vi phenoxyethyldimethylamine, '74 parts of phenoxyethoxyethyl bromide, and 158 parts ofaceto -j nitrile. The mixture was stirred and heated at -85 C. for 6.5hours. The solvent was stripped off under reduced pressure. The residuewas taken up in hot ethyl acetate, cooled, and crystallized. The yieldwas parts of diisobutyl; phenoxyethyl dimethyl phenoxyethoxyethyl am;monium bromide. I

-It has a phenol coefiicient of 425 against Sal;- monella typhz'. and of625 againstStaphylococcas.

aureus.

Example 7 Staphylococcus aareus.

Example 8 'There were mixed 39 parts by weight of p- 1,1,3,3tetramethylbutylphenoxyethoxyethoxyethyl dimethylamine, '21 parts ofphenoxyethyl'f bromide, and 60 parts of acetonitrile. The mix-f ture wasstirred and heated for four and a half hours under reflux. The solventwas evaporated, under reduced pressure to give a residue which." wastaken up iii ethyl a'cetate -anderystallizedh The mixture was stirredand heated under" The phenol coefiicients for this compound were 225against Salmonella typhi and 330 against Staphylococcus aureus.

Example 9 There were mixed 169 parts of p-1,1,3,3-tetra-'methylbutylphenoxyethoxyethyl dimethylamine and 95 parts ofphenylthioethyl chloride and 20' The parts of nitromethane was addedthereto. mixture was heated on a steam bath for '78 hours and strippedof solvent. The residue was taken up in ethyl acetate and crystallizedtherefrom. The yield was 90 parts of tetramethylbutylphenoxyethoxyethylphenylthioethyl dimethyl ammonium chloride.

It was found to have a phenol coefficient of 275 against Salmonellatyphi and 570 against Staphylococcus aureus.

The phenylthioethyl chloride used above was prepared by the reaction of55 parts of thiophenol and 42 parts of ethylene chlorohydrin in 150parts of methanol in which 11.5 parts of sodium had been dissolved. Thisformed sodium chloride, which was filtered oif, and phenylthioethylalcohol, which was distilled at 125 C.-131 C./6 mm. This was convertedto the chloride by passing hydrogen chloride into it on the steam bathfor four hours. distilled at 110 C.-119 C./9 mm.

Example 10 There were mixed 111 partsof phenylthioethyl bromide, 169parts of 1,1,3,3-tetramethylbutylphenoxyethoxyethyl dimethylamine, and49 parts of ethyl acetate. The mixture was refluxed for about fourhours. Crystals formed when the reaction mixture was cooled. These wereseparated, washed, and air-dried. They corresponded in composition to C3 CH3 Evaluation of this compound against Salmonella typhi andStaphylococcus aureus gave phenol coefficients of 435 and 5'70respectively.

In testing the compounds of this invention bactericidal efficiency wasmeasured in a number of ways and against various organisms. Phe- Thedesired product was i showing no growth was taken'as the end-point ofbactericidal action.

Fungitoxicity tests were made by the slide germination technique with Macrosporium sarcmaeforme and Sclerotinia fructicola as the testorganisms. A 100% inhibition of germination of spores was obtained at 1to 200,000 dilution with tetramethylbutylphenoxyethoxyethyl phenoxyethyldimethyl ammonium bromide. Results with other compounds of this type areall of the same order. A spray containing one pound oftetramethylbutylphenoxyethoxyethyl phenoxyethyl dimethyl ammoniumbromide dispersed in 100 gallons of water was applied to celery. Only18% of the thus-treated plants showed signs of Sercospora blight while95% of the control plants were diseased. v

The data which have been obtained coupled with favorable propertieswhich have been described above establish the compounds of thisinvention as valuable and useful. Of particular interest are thosecompounds in which A of the general formula is hydrogen, since thesehave I101 coefficients were determined by the F. D. A. 7

method at 20 C. and represent the ratio of effective dilution of thecompound under test to the efiective dilution of phenol.

Tests were also run against pathogenic organisms by a dilution methodutilizing trypticasesoy broth. One per cent solutions of the productunder test were diluted with broth and several dilutions autoclaved forten minutes at 10 to 12 lbs. pressure. The dilutions were cooled andinoculated with a 4 mm. loopful of a test organism culture. Incubationwas carried out at 37 C. for 24 hours. The highest dilution showing nogrowth gave the end-point for bacteriostatic action. After an additional24 hours of incubation at 37 C. subcultures were made by transferringthree loopfuls from cultures showing no growth to freshtrypticase-soybroth. The subcultures were incubated 48 hours. The highest dilution ahighly favorable combination of properties. The bromides seem to beparticularly mild and non-irritating and yet are quite as potent againstbacteria and fungi as the-chlorides on a weight basis.

We claim:

1. As a new chemical substance, a compound of the formula is an integerfrom one to three, and m is an integer from one to two.

2. A compound of the formula CH3 CH3 C6H13CHCH3 where X is a halogen.

LOUIS H. BOCK. LEO S. LUSKIN.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Name Date Bruson Apr. 26, 1938 OTHER REFERENCES,J. Am. Pharmaceutical Assn, Proc. Pharm. Edit, Dec. 1946, p. 560.

Number

1. AS A NEW CHEMICAL SUBSTANCE, A COMPOUND OF THE FORMULA